In the U.S., the morbidity associated with infection of healthy individuals by human rhinovirus (RV) represents a major health concern. Furthermore, recent studies suggest that up to 80 percent of asthma exacerbations are associated with upper respiratory infections. Despite the fact that early epidemiologic evidence and more recent laboratory-based studies implicate environmental oxidant pollutants, such as 03, in increases in the severity of viral disease, the mechanisms underlying such an interaction have not been identified. The proposed studies will test the HYPOTHESIS that exposure of allergic asthmatic subjects to ambient levels of 03 directly enhances viral disease by exacerbating the virus-induced inflammatory response and by amplifying lower airway obstruction. We have used data from in vitro studies of human airway epithelial cells and controlled human exposures to design experiments in human subjects which will investigate the mechanisms through which 03 modulates (i) the virus-induced expression and release of specific inflammatory mediators by airway cells, (ii) the severity of the resultant airway viral infection, and (iii) an increase in lower airway symptoms in the absence of infection. We will address three SPECIFIC AIMS and determine (1) in the upper respiratory system of asthmatics, the effect of previous 03 exposure on RV16-induced stimulation of inflammatory mediator gene expression, mediator release and cell recruitment, (2) in the lower airways of asthmatics, the effect of previous O3 exposure on RV16-induced stimulation of inflammatory mediator gene expression, mediator release and cell recruitment and on airway responsiveness, and (3) if the persistent small airways dysfunction and inflammation that is caused by repeated, daily O3 exposure influence lower airway symptoms induced by RV16 infection. These studies will directly test the presence of the proposed key interaction between O3 and RV in human airways already compromised by existing disease and will provide insight regarding the mechanisms underlying this interaction. This information will improve our understanding of the risk associated with environmental oxidant pollutant exposure in this population of individuals in whom rhinoviral infection may represent a significant health concern.